At the annual meeting of the Association for Molecular Pathology this week, Illumina sponsored a panel in which leaders in the field discussed practical, reimbursement, and other considerations for labs implementing clinical next-gen sequencing.

During AMP's corporate workshops, Illumina’s Kirk Malloy introduced and guided the three-member panel — Charles Mathews of Boston Healthcare Associates, Suzanne Kamel-Reid of Toronto’s University Health Network, and Marisa Needham from Duke University — who spoke to the reimbursement and economic value, the real-world actionability, and the nuts and bolts of implementing and validating clinical NGS.

The question of validating sequencing against orthogonal technologies.

With NGS entering the clinic, labs must find ways to demonstrate that this newer technology is equivalent and valid compared to a gold standard. However, the increased sensitivity of NGS relative to older methods like Sanger sequencing can make direct comparison difficult or impossible.

"Sanger is going to be difficult, for example, if you are looking at variants with a low frequency," Needham said. In light of this, at UVA, she said, the team looked to other methods, like pyrosequencing, against which to validate their new NGS strategies. At Duke, meanwhile, the lab is working with locked nucleic acid primers to increase Sanger sensitivity, she said.

The question of whether there is a need for matched tumor and normal sequencing also came up in the panel discussion.

Tumor versus germline sequencing is an issue that has come to the fore in the NGS field since a publication by Johns Hopkins researchers earlier this year, which concluded that tumor-only analysis "may lead to inappropriate administration of cancer therapies with substantial effects on patient safety and healthcare costs."

“We do [sequence matched normal DNA] and I think it's extremely important for larger panels,” Kamel-Reid said. “But for the smaller panels [like the] TruSight 26-gene panel we are not. We don’t need to. I think we know what we expect to see and if we see something unusual we could then get a blood or a buccal swab.”

“Another thing we do is use our own data to teach ourselves about variants we see frequently, using data amassed over thousands of samples to build a database so we can avoid having to do matched normal sequencing,” she said.

The question of implementation has also come to encompass bioinformatic strategies

As NGS has opened the door to much more comprehensive genomic analyses than previous technologies, the question of implementation has also come to encompass bioinformatic strategies that had little place in these practical considerations even just a few years ago.

The new role of bioinformatics also has a connection to the question of value and reimbursement, Mathews said. As part of a project for AMP aimed at studying in detail the value and costs of clinical sequencing.

"The question of implementation raises a huge point," Needham said. "At UVA there was very little bioinformatics support in house so we had to outsource it."

The questions of actionability and value were also closely intertwined

"From my perspective something that is clinically actionable not only impacts information about pathogenicity, but anything that would alter patient management as well, so whether it is druggable, or prognostic, or aids in diagnosis, or helps you determine predisposition in a family. There are a lot of different definitions of actionability," Kamel-Reid said. However, this expansive view of clinical utility has made it difficult for the lab community to make the case for NGS to payors, Mathews responded.

Finally, all on the panel agreed that the laboratory and clinical community must do a better job of collecting data that reflects on tests' real-world impact and practical value.